title: Attenuation of streptozotocin-induced diabetic retinopathy with low molecular weight fucoidan via inhibition of vascular endothelial growth factor.
abstract: Diabetic retinopathy (DR) is a hyperglycemia-induced ischemic disorder characterized by microvascular dysfunction and neovascularization. It is a leading cause of blindness in many countries, yet efficient drugs are limited now for prevention and treatment of DR. Low molecular weight fucoidan (LMWF), extract from brown algae, has been shown to possess multiple biological activities like anti-inflammation, anti-oxidation and anti-aggregation, which all could be beneficial for attenuating ischemia-induced tissue damages. Here, by comparing with calcium dobesilate, the potent antioxidant compound currently used for the treatment of DR, we investigated the protective effect of LMWF against DR in streptozotocin-induced diabetic mice and high glucose-promoted vascular endothelial growth factor (VEGF) production and cell proliferation in microvascular endothelial cells. One week after diabetes induction, the mice were administered with LMWF (50, 100 or 200 mg/kg/day) or calcium dobesilate (200 mg/kg/day) for four months, then the retinal pathological changes and neovascularization were detected by hematoxylin-eosin staining and fluorescein dextran angiography, respectively. Immunofluorescence staining, ELISA and RT-PCR were used to examine the expression levels of hypoxia-inducible factor-1α (HIF-1α) and VEGF in retina and endothelial cells. Here, we found that LMWF resembled calcium dobesilate, in alleviating retinal pathological change and hindering neovascularization due to diabetes in vivo. The relative levels of VEGF expression and HIF-1α induction were also less in retinas of LMWF- or calcium dobesilate-treated diabetic mice than those in retinas of control mice. Furthermore, high glucose-induced VEGF overexpression and cell proliferation in primary cultured vascular endothelial cells were also inhibited by LMWF in a dose-dependent manner. Therefore, this study demonstrated that LMWF alleviates diabetic retinal neovascularization and damage likely through lowering HIF-1α and VEGF expressions, providing a potential candidate drug for prevention and treatment of diabetic retinopathy.
authors.affiliation: Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Street of Youanmenwai, #10 Xitoutiao, District of Feng Tai, Beijing 100069, PR China.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Yang
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Yu
authors.forename: Quanbin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Wentong
authors.initials: W
authors.lastname: Cui
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Dali
authors.initials: D
authors.lastname: Luo
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D002123:Calcium Dobesilate / Q000494:pharmacology; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005451:Fluorescein Angiography; D019084:Fluorescent Antibody Technique, Indirect; D006490:Hemostatics / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011134:Polysaccharides / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012171:Retinal Vessels; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D006490:Hemostatics; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011134:Polysaccharides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002123:Calcium Dobesilate; C007789:fucoidan
keywords: diabetic retinopathy; high glucose; hypoxia-inducible factor-1α; low molecular weight fucoidan; vascular endothelial cells; vascular endothelial growth factor